Increased lung expansion alters lung growth but not alveolar epithelial cell differentiation in newborn lambs (original) (raw)
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Effect of Increased Lung Expansion on Surfactant Protein mRNA Levels in Lambs
Pediatric Research, 2001
Increased fetal lung expansion profoundly inhibits surfactant protein gene expression and stimulates cellular proliferation in the fetal lung. Our aim was to determine whether increased expansion of the lung after birth, by the application of a continuous positive airway pressure (CPAP) for 12 h, inhibits surfactant protein gene expression and stimulates cell division in lambs. Two week-old lambs were randomly divided into 2 groups (n ϭ 5 for each), sedated, and exposed to either no CPAP (controls) or 10cmH 2 O of CPAP during a 12-hour treatment period. After 2 h of the treatment, 3 H-thymidine was administered to each lamb (iv) to measure pulmonary DNA synthesis rates over the following 10 h of treatment. To assess the increase in lung expansion, functional residual capacity (FRC) was measured before the start of the treatment period and again at 6 and 12 h. Compared with control lambs, a CPAP of 10 cmH 2 O increased FRC from 26.8 Ϯ 3.8 mL/kg to 62.9 Ϯ 19.7 mL/kg at 6 h and it remained elevated at 12 h (56.2 Ϯ 5.7 mL/kg). Despite this large increase in end expiratory lung volume (FRC), the mRNA levels for SPA , SP-B, and SP-C and DNA synthesis rates in lung tissue were not altered. The results of this study indicate that, in contrast to the fetus, an increase in end expiratory lung volume of 100% does not affect surfactant protein gene expression or pulmonary DNA synthesis rates in 2 week old lambs. Thus, the response of the lung to increases in lung expansion varies markedly before and after birth. (Pediatr Res 50: 720-725, 2001) Abbreviations CPAP, continuous positive airway pressure FRC, functional residual capacity SP, surfactant protein PEEP, positive end expiratory pressure PaCO 2 , partial pressures of carbon dioxide in arterial blood PaO 2 , partial pressure of oxygen in arterial blood SaO 2 , percentage oxygen saturation of Hb in arterial blood
Changes in alveolar epithelial cell proportions during fetal and postnatal development in sheep
American journal of physiology. Lung cellular and molecular physiology, 2003
Basal lung expansion is an important determinant of alveolar epithelial cell (AEC) phenotype in the fetus. Because basal lung expansion increases toward term and is reduced after birth, we hypothesized that these changes would be associated with altered proportions of AECs. AEC proportions were calculated with electron microscopy in fetal and postnatal sheep. Type I AECs increased from 4.8 +/- 1.3% at 91 days to 63.0 +/- 3.6% at 111 days of gestation, remained at this level until term, and decreased to 44.8 +/- 1.8% after birth. Type II AECs increased from 4.3 +/- 1.5% at 111 days to 29.6 +/- 4.1% at 128 days of gestation, remained at this level until term, and then increased to 52.9 +/- 1.5% after birth. Surfactant protein (SP)-A, -B and -C mRNA levels increased with increasing gestational age before birth, but the changes in SP expression after birth were inconsistent. Thus before birth type I AECs predominate, whereas after birth type II AECs predominate, possibly due to the redu...
The Journal of Physiology, 2002
After birth, the efficient exchange of respiratory gases is dependent upon the alveolar epithelium containing appropriate proportions of type-I and type-II alveolar epithelial cells (AECs). Type-I AECs are large, flattened cells that have long cytoplasmic extensions that extend over much of the surface area of the lung, providing the vast majority of the epithelial component of the air-blood gas barrier (Schneeberger, 1997). Type-II AECs are rounded in shape and contain cytoplasmic organelles (lamellar bodies), which are the intracellular storage sites for surfactant. In addition to producing and releasing surfactant, type-II AECs are thought to be the progenitor cell type that gives rise to both phenotypes (Mason & Shannon, 1997). Although both AEC types are critical for respiratory function after birth, little is known about the factors that control differentiation into either phenotype in vivo. Previous research has focussed predominantly on the endocrine regulation of AECs, although more recently, attention has focussed on the impact of mechanical forces on AEC phenotypes (
PLOS ONE
Intrauterine growth restriction (IUGR) induced by placental restriction (PR) in the sheep negatively impacts lung and pulmonary surfactant development during fetal life. Using a sheep model of low birth weight (LBW), we found that there was an increase in mRNA expression of surfactant protein (SP)-A,-B and-C in the lung of LBW lambs but no difference in the protein expression of SPA orB. LBW also resulted in increased lysosome-associated membrane glycoprotein (LAMP)-3 mRNA expression, which may indicate an increase in either the density of type II Alveolar epithelial cells (AEC) or maturity of type II AECs. Although there was an increase in glucocorticoid receptor (GR) and 11β-hydroxysteroid dehydrogenase (11βHSD)-1 mRNA expression in the lung of LBW lambs, we found no change in the protein expression of these factors, suggesting that the increase in SP mRNA expression is not mediated by increased GC signalling in the lung. The increase in SP mRNA expression may, in part, be mediated by persistent alterations in hypoxia signalling as there was an increase in lung HIF-2α mRNA expression in the LBW lamb. The changes in the hypoxia signalling pathway that persist within the lung after birth may be involved in maintaining SP production in the LBW lamb.
Alterations in lung expansion affect surfactant protein A, B, and C mRNA levels in fetal sheep
American Journal of Physiology-Lung Cellular and Molecular Physiology, 1999
Obstruction of the fetal trachea is a potent stimulus for fetal lung growth, and it has been suggested that this procedure may be used therapeutically to reverse lung growth deficits in human fetuses with lung hypoplasia. However, little is known about the effects of increased lung expansion on other aspects of lung development. Our aim was to determine the effect of increased and decreased lung expansion on the mRNA levels encoding surfactant protein (SP) A, SP-B, and SP-C in ovine fetal lungs. Lung tissue samples were collected from fetuses exposed to 2, 4, or 10 days of increased lung expansion caused by tracheal obstruction. The mRNA levels for SP-A, SP-B, and SP-C were determined by Northern blot analysis with specific ovine cDNA probes; SP-A protein levels were determined by Western blot analysis. Compared with age-matched (128-day gestational age) control fetuses, SP-A, SP-B, and SP-C mRNA levels in fetal lung tissue were significantly reduced at 2 days of tracheal obstructio...
Pediatric Research, 2006
As the transition to extrauterine life at birth alters the proportions of type I and II alveolar epithelial cells (AECs), our aim was to determine the effect of mild preterm birth on AECs and surfactant protein (SP) gene expression. Preterm lambs were born at ϳ133 d of gestational age (DGA); controls were born at term (ϳ147 DGA). Lungs were collected from preterm lambs at termequivalent age (TEA; ϳ2 wk after preterm birth) and 6 wk post-TEA. Control lung tissue was collected from fetuses (at 132 DGA), as well as from lambs at ϳ6 h (normal term) and 2, 6, and 8 wk of postnatal age (PNA). In controls, the proportion of type I AECs decreased from 65.1 Ϯ 3.9% at term to 50.9 Ϯ 3.3%, while the proportion of type II AECs increased from 33.7 Ϯ 3.9% to 48.5 Ϯ 3.3% at 6 wk PNA. At 2 wk after preterm birth, the proportions of type I and II AECs were similar in preterm lambs compared to 132-d fetal levels and term controls but differed from control values at 2 wk PNA; differences between control and preterm lambs persisted at 8 wk PNA. At ϳ2 wk after preterm birth, SPA and SP-B, but not SP-C, mRNA levels were significantly reduced in preterm lambs compared with term controls, but these differences did not persist at 2 and 6 wk PNA. We conclude that mild preterm birth alters the normal postnatal changes in type I and II cell proportions but does not severely affect SP gene expression.
American journal of physiology. Lung cellular and molecular physiology, 2000
Type I and type II alveolar epithelial cells (AECs) are derived from the same progenitor cell, but little is known about the factors that regulate their differentiation into separate phenotypes. An alteration in lung expansion alters the proportion type II AECs in the fetal lung, indicating that this may be a regulatory factor. Our aim was to quantify the changes in the proportion of type I and type II AECs caused by increased fetal lung expansion and to provide evidence for transdifferentiation of type II into type I cells. Lung tissue samples were collected from ovine fetuses exposed to increased lung expansion induced by 2, 4, or 10 days of tracheal obstruction (TO). The identities and proportions of AEC types were determined with electron microscopy. The proportion of type II cells was reduced from 28.5 +/- 2.2% in control fetuses to 9.4 +/- 2.3% at 2 days of TO and then to 1.9 +/- 0.8% at 10 days. The proportion of type I AECs was not altered at 2 days of TO (63.1 +/- 2.3%) com...
AJP: Lung Cellular and Molecular Physiology, 2011
The initiation of ventilation in preterm, surfactant-deficient sheep without positive end-expiratory pressure (PEEP) causes airway injury and lung inflammation. We hypothesized that PEEP and surfactant treatment would decrease the lung injury from initiation of ventilation with high tidal volumes. Fetal sheep at 128-day gestational age were randomized to ventilation with: 1) no PEEP, no surfactant; 2) 8-cmH2O PEEP, no surfactant; 3) no PEEP + surfactant; 4) 8-cmH2O PEEP + surfactant; or 5) control (2-cmH2O continuous positive airway pressure) ( n = 6–7/group). After maternal anesthesia and hysterotomy, the head and chest were exteriorized, and the fetus was intubated. While maintaining placental circulation, the fetus was ventilated for 15 min with a tidal volume escalating to 15 ml/kg using heated, humidified, 100% nitrogen. The fetus then was returned to the uterus, and tissue was collected after 30 min for evaluation of early markers of lung injury. Lambs receiving both surfactan...
Journal of Applied Physiology, 2003
Prolonged fetal tracheal occlusion (TO) accelerates lung growth but leads to loss of alveolar epithelial type II (AE2) cells. In contrast, temporary TO leads to recovery of AE2 cells and their ability to produce surfactant. The aim of this study was to determine the effects of temporary TO in fetal sheep with lung hypoplasia on postnatal lung function, structure, and surfactant protein mRNA expression. Diaphragmatic hernia (DH) was created in 22 fetal sheep at 65 days of gestation. TO was performed between 110 days of gestation and full term (DH/TO, n = 7) and between 110 and 130 days of gestation (DH/TO+R, n = 6). Sham-operated fetuses ( n = 11) served as controls. Lambs were delivered at ∼139 days of gestation, and blood gas tensions were monitored over a 2-h resuscitation period. Temporary TO increased growth of the hypoplastic lung and restored surfactant protein mRNA expression and AE2 cell density but did not improve respiratory function above that of animals that underwent pr...
AJP: Lung Cellular and Molecular Physiology, 2004
Our aim was to determine whether cortisol's effect on alveolar epithelial cell (AEC) phenotypes in the fetus is mediated via a sustained alteration in lung expansion. Chronically catheterized fetal sheep were exposed to 1) saline infusion, 2) cortisol infusion (122–131 days' gestation, 1.5–4.0 mg/day), 3) saline infusion plus reduced lung expansion, or 4) cortisol infusion plus reduced lung expansion. The proportions of type I and II AECs were determined by electron microscopy, and surfactant protein (SP)-A, -B, and -C mRNA levels were determined by Northern blot analysis. Cortisol infusions significantly increased type II AEC proportions (to 38.2 ± 2.2%), compared with saline-infused fetuses (23.8 ± 2.4%), and reduced type I AEC proportions (to 59.0 ± 2.2%), compared with saline-infused fetuses (70.4 ± 2.4%). Reduced lung expansion also increased type II AEC proportions (to 52.9 ± 3.5%) and decreased type I AEC proportions (to 34.2 ± 3.7%), compared with control, saline-inf...